1. Field of the Invention
The present invention relates to the use of vinca alkaloids in combatting tumors.
2. Discussion of the Background
The dimeric alkaloids, vincristine and vinblastine, containing indol-indoline moieties from Catharanthus species are widely used as antitumor agents, singly or in combination with other chemotherapeutic agents. Vincristine has demonstrated substantial activity against non-Hodgkin's and Hodgkins lymphomas, acute lymphoblastic leukemia, Wilm's tumor, rhabdomyosarcoma, and neuroblastoma.
The vinca alkaloids possess cytotoxic activity by virtue of their binding to tubulin. The latter is a dimeric protein found in the soluble fraction of the cytoplasm of all cells. It exists in equilibrium with a polymerized form, the microtubular apparatus which forms the spindle along which chromosomes migrate during mitosis. In addition, microtubules play a vital role in maintaining cell structure, providing a conduit for cellular secretions and for neurotransmitters transit along axons. The vinca alkaloids, through their binding to tubulin, inhibit the process of assembly of microtubules and lead to the dissolution of the mitotic spindle.
The clinical use of vincristine is highly compromised because of treatment-limiting toxicities. Total doses of vincristine in excess of 2 mg are often associated with a progressive and disabling neurotoxicity. The first signs of neuropathy are a decrease in deep tendon reflexes and paresthesias of the fingers and lower extremeties. More advanced neurotoxicity may lead to cranial nerve palsics and profound weakness of the dorsiflexors of the foot and extensors of the wrist. At higher doses of vincristine, above 3 mg total dose, constipation, obstipation and paralytic ileus may occur because of autonomic neuropathy.
The vincristine alkaloid, like many other antineoplastic drugs, fails to discriminate efficiently between normal and target tissues. A system enabling such chemotherapeutic agents to reach their target in a selective and controlled fashion would represent a substantial advance in cancer chemotherapy.